Our goal is to investigate the molecular mechanism that SYNJ1/PARK20 contributes to the pathogenesis of Parkinson's disease (PD) and understand if SYNJ1 is involved in the common PD pathogenic pathway. The available evidence suggests that diverse cellular functions are involved in PD pathogenic pathways, including synaptic trafficking and autophagy-lysosome. SYNJ1 encodes synaptojanin1 (synj1), a phosphoinositide phosphatase and a binding partner for endophilinA. The synj1 is enriched in nerve terminals where it regulates synaptic vesicle (SV) recycling and synaptic protein targeting by hydrolyzing membrane phosphoinositides via its two phosphatase domains (SAC1 and the 5-phosphatase) and by binding to endophilinA. At least three recessive point mutations located in the SAC1 or 5-phosphatase domain of the SYNJ1 gene, are linked to the Parkinsonism. We further showed that R258Q mutation abolishes SAC1 phosphatase activity of synj1, suggesting a loss of function of synj1 responsible for the disease. Mice carrying R258Q mutant of synj1 develop dystrophic terminals selectively in the nigral DAergic neurons and impaired SV recycling, confirming the causality of the mutation to the disease and suggesting selective effect of SYNJ1 dysfunction in DAergic neurons. While the pathogenic variants of SYNJ1 and other recessive PD genes are extremely rare, whether they are involved in the more common form of PD (idiopathic) remains unclear. We reported that SYNJ1 heterozygous deletion (SYNJ1+/-) midbrain DAergic neurons display slowed SV endocytosis, and our preliminary study of SYNJ1+/- mice show reduced striatal DA content and reduced density of DAergic nerve terminal in an age dependent manner. The result suggests haploinsufficiency of SYNJ1 leads to dysfunctional DAergic neuron terminal dystrophy. Furthermore, we found down-regulation of human SYNJ1 transcripts in sporadic PD brains, raising a possibility that SYNJ1 deficiency is linked to the pathogenic pathway of more common PD. We hypothesize that reduced expression of SYNJ1 predispose DAergic neuron to dystrophic terminal degeneration and neurotoxicity underlying PD pathogenesis. We will investigate the two aims: Aim 1. To validate the hypothesis that haploinsufficiency of SYNJ1 contributes to progressive DAergic neuron vulnerability and PD related symptoms in animal models; Aim 2. To determine that reduced SYNJ1 expression in human iPSC DAergic neurons causes presynaptic vulnerability and PD related pathogenic process. Therefore, our study not only will provide an insight into the molecular mechanism for SYNJ1 rare mutation related Parkinsonism, but importantly may also reveal the pathogenic mechanism for more common form of PD (idiopathic) and identify novel therapeutic targets in regulating phosphoinositide levels.